Identification of Sox9-Dependent Acinar-to-Ductal Reprogramming as the Principal Mechanism for Initiation of Pancreatic Ductal Adenocarcinoma

被引：534

作者：

Kopp, Janel L. ^{[2
,3
]}

von Figura, Guido ^{[1
]}

Mayes, Erin ^{[2
,3
]}

Liu, Fen-Fen ^{[2
,3
]}

Dubois, Claire L. ^{[2
,3
]}

Morris, John P. ^{[1
]}

Pan, Fong Cheng ^{[4
]}

Akiyama, Haruhiko ^{[5
]}

Wright, Christopher V. E. ^{[4
]}

Jensen, Kristin ^{[6
,7
]}

Hebrok, Matthias ^{[1
]}

Sander, Maike ^{[2
,3
]}

机构：

[1] Univ Calif San Francisco, Dept Med, Ctr Diabet, San Francisco, CA 94143 USA

[2] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[4] Vanderbilt Univ, Dept Cell & Dev Biol, Nashville, TN 37232 USA

[5] Kyoto Univ, Dept Orthoped, Sakyo Ku, Kyoto 6068507, Japan

[6] Vet Affairs Palo Alto Hlth Care Syst, Dept Pathol, Stanford, CA 94305 USA

[7] Stanford Univ Hosp, Stanford, CA 94305 USA

来源：

CANCER CELL | 2012年 / 22卷 / 06期

关键词：

TRANSCRIPTION FACTORS; EGF RECEPTOR; CELL; KRAS; SOX9; NOTCH; ENDOCRINE; ORIGIN; EXPANSION; LINEAGE;

D O I：

10.1016/j.ccr.2012.10.025

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Tumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.

引用

页码：737 / 750

页数：14

共 59 条

[1] Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma [J].

Aguirre, AJ ;

Bardeesy, N ;

Sinha, M ;

Lopez, L ;

Tuveson, DA ;

Horner, J ;

Redston, MS ;

DePinho, RA .

GENES & DEVELOPMENT, 2003, 17 (24) :3112-3126

[2] EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis [J].

Ardito, Christine M. ;

Gruener, Barbara M. ;

Takeuchi, Kenneth K. ;

Lubeseder-Martellato, Clara ;

Teichmann, Nicole ;

Mazur, Pawel K. ;

DelGiorno, Kathleen E. ;

Carpenter, Eileen S. ;

Halbrook, Christopher J. ;

Hall, Jason C. ;

Pal, Debjani ;

Briel, Thomas ;

Herner, Alexander ;

Trajkovic-Arsic, Marija ;

Sipos, Bence ;

Liou, Geou-Yarh ;

Storz, Peter ;

Murray, Nicole R. ;

Threadgill, David W. ;

Sibilia, Maria ;

Washington, M. Kay ;

Wilson, Carole L. ;

Schmid, Roland M. ;

Raines, Elaine W. ;

Crawford, Howard C. ;

Siveke, Jens T. .

CANCER CELL, 2012, 22 (03) :304-317

[3] SOX9cre1, a cis-acting regulatory element located 1.1 Mb upstream of SOX9, mediates its enhancement through the SHH pathway [J].

Bien-Willner, Gabriel A. ;

Stankiewicz, Pawe ;

Lupski, James R. .

HUMAN MOLECULAR GENETICS, 2007, 16 (10) :1143-1156

[4]

Brembeck FH, 2003, CANCER RES, V63, P2005

[5] The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia [J].

Carriere, Catherine ;

Seeley, Elliott S. ;

Goetze, Tobias ;

Longnecker, Daniel S. ;

Korc, Murray .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (11) :4437-4442

[6] Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras [J].

Carriere, Catherine ;

Young, Alison L. ;

Gunn, Jason R. ;

Longnecker, Daniel S. ;

Korc, Murray .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2009, 382 (03) :561-565

[7]

Cornish Toby C, 2011, Surg Pathol Clin, V4, P523, DOI 10.1016/j.path.2011.03.005

[8] Notch and Kras in pancreatic cancer At the crossroads of mutation, differentiation and signaling [J].

De La O, Jean-Paul ;

Murtaugh, L. Charles .

CELL CYCLE, 2009, 8 (12) :1860-1864

[9] sox9b Is a Key Regulator of Pancreaticobiliary Ductal System Development [J].

Delous, Marion ;

Yin, Chunyue ;

Shin, Donghun ;

Ninov, Nikolay ;

Carten, Juliana Debrito ;

Pan, Luyuan ;

Ma, Taylur P. ;

Farber, Steven A. ;

Moens, Cecilia B. ;

Stainier, Didier Y. R. .

PLOS GENETICS, 2012, 8 (06)

[10] Preexisting pancreatic to acinar cell, but not islet β cell, regeneration [J].

Desai, Biva M. ;

Oliver-Krasinski, Jennifer ;

De Leon, Diva D. ;

Farzad, Cyrus ;

Hong, Nankang ;

Leach, Steven D. ;

Stoffers, Doris A. .

JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (04) :971-977

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